2-methyl-3-(beta-chloroethyl)-4, 6-dichloro pyridine and method of making same



United States Patent 2-METHYL-3-([i-CHLORQETHYL)-4,6-DICHLORO PYRIDINEAND METHOD OF MAKING SAME Andrew N. Wilson, Colonia, and Stanton A.Harris, Westfield, N. J., assignors to Merck & C.o., Inc., Rahway, N.J., a corporation of'New Jersey NoDrawing. Application september 27,195i), Serial No; 187,158

9 Claims. (Cl. 260290) This invention relates to the new chemicalcompound, 2-methyl-3-(fl-chloroethyl):4,6-dichlorop-yridine, a methodfor its preparation, and processes for converting this compound to2-methyl-3 (fi-chloroethyl)pyridine.

in a process described in J. Org. Chem. 6, 54 (1941),2-methyl-'3-(,B-chloroethyl)pyridine was obtained from 2-methyl-S-([i-ethoxyethyl) 4,6 dihydroxypyridine by a three step processcomprising, refluxingsaid starting material with phosphorus oxychlorideto form 2-methyl-3- (B'ethoxyethyl)-4,6dichloropyridine, reducing thiscompound with hydrogen in the presence of a hydrogenation catalyst toobtain Z-methyl 3 (,B-ethoxyethyl)-pyridine which on treatment withconcentrated hydrochloric acid was converted to the desired compound.The Z-methyl- 3-(B-chloroethyl)pyridine may then be converted byhydrolysis to obtain 2-methyl-3-(B-hydroxymethyl)@pyridine which isauseful intermediate in the synthesis of neopyrithiamine, the pyridineanalog of thiamine. This pyridine analog of thiamine possesses markedand effective antivitamin activity.

This invention is concernedwith an improved process for preparing2-methyl-3-(fi-chloroethyl)-pyridine. It is one object of this inventionto provide a new pyridine derivative, 2 methyl-3-( 3-chloroethyl)-4,6-dichloropyridine, which is a useful intermediate in preparingZ-methyl- 3-(B-chloroethyl)-pyridine. It is a further object to providea method for obtaining this new compound. Another object is to provide aprocess 'for converting our new compound to2-methyl-3-(fi-chloroethyl)-pyridine. Other objects will be apparentfrom the detailed description hereinafter provided.

in accordance with our present invention, we have found that2-methyl-3-( 8 cliloroethyl)-pyridine is more readily and convenientlyobtained by a two step process which may be illustrated as followsfwherein R representsan alkylgroup.

In the firstste of our process, the2-methyl-3-(palkoxyethyl)-4,6-dihydroxypyridine is reacted with achlorinating agent such as phosphorus oxychloride, phosphoruspentachloride, and the'like at elevated temperature under p phericpressure to :produce 2-methyl-3- (,B-chloroethyl)-4,6-dichloropyridine.This step is conveniently accomplished by heating the chlorinating agentand the 2-methyl-3-(p-alkoxyethyl) 4,6 dihydroxypyridine in a pressurevessel for sufi'icient time to effect the desired reaction. In carryingout this reaction with 2- methyl-3 3-ethoxyethyl -4,6-dihydroxypyridineutilizing phosphorus oxychloride as the chlorinating agent, we haveobtained excellent yields of the desired product by reacting thesesubstances together at about 140 C. for 6 hours. Similarly, other,B-alkoxy derivatives may be used in place of the B-ethoxy derivative.

After cooling the resulting reaction mixture, the 2-methyl-3-(fi-chloroethyl)-4,6-dichloropyridine is readily recovered byevaporating any excess chlorinating agent 2,695,902 Patented Nov. 30,1954 and volatile byproducts under diminished pressure, dissolving theresidue in water, and cooling the resulting aqueous solution to causeprecipitation of the product in crystalline form. The product may thenbe removed and dried. Any residual traces of the product in the motherliquor may be recovered by extraction with a water-immiscible solventsuch as chloroform, and obtained in solid form by concentratingthe'chloroform extracts to dryness. if desired, the final product may befurther purified by recrystallization from suitable organic solventssuch as methyl alcohol, ethyl alcohol, isopropyl alcohol, and the like.

The 2-methyl-3-(fl-chloroethyl)-4,6-dichloropyridine is obtained in theform of a white solid having a melting point of about 5556 C.

In accordance with a further embodiment of our invention, this productis readily converted by reduction with hydrogen in the presence of ahydrogenation catalyst to 2 -methyl-3-(,B-chloroethyl)-pyridine. This isconveniently accomplished by intimately contacting a solution of thecompound in an inert solvent such as methanol, ethanol, and the likewith hydrogen in the presence of a hydrogenation catalyst. We haveobtained particularly good yields of product by carrying out thisreduction in the presence of a catalyst consisting of palladiumsuspended on barium sulfate. Similarly, other salts or oxides ofpalladium or solid palladium itself are equally suitable as catalystsfor this reaction.

The 2-methyl-3-(fl-chloroethyl)-pyridine is recovered from thehydrogenation mixture by removing the suspended catalyst andconcentrating the solution to dryness under reduced pressure. Theidentity of this substance was established by preparing thecorresponding picric acid salt.

it is indeed surprising that this reduction can be effected withoutreducing the fi-chloro substituent since it would have been anticipatedthat this chlorine would be most readily reduced forming an ethyl groupunder these reaction conditions.

As was indicated previously, the 2-methyl-3-(B-chloroethyl)-pyr idinemay be readily hydrolyzed to obtain the corresponding B-(B-hydrbxyethyl)compound which is useful as an intermediate for preparingneopyrithiamine and other compounds.

The following examples are presented to illustrate specific embodimentsof our invention:

Example 1 Five grams of 2-methyl-3-(B-ethoxyethyl)-4,6-dihydroxypyridinewas dissolved in 25 ml. of freshly distilled phosphorus oxychloride. Asmall amount of heat was evolved but there was no obvious evolution ofhydrogen chloride. The solution was sealed in a combustion tube andheated at C. for six hours. The excess phosphorus oxychloride wasremoved by distillation under reduced pressure, and to the residue wasadded a large excess of crushed ice so that no heating occurred. Theproduct separated as a crystalline solid. It may be obtainedbylfiltration and purified by recrystallization from alcohol; or it maybe obtained by steam distillation from the mixture, which has been madealkaline with potassium hydroxide. The yield of2-methyl-3-(B-chloroethyl)-4,6- dichslgroryridine was 4.8 g. (84% of thetheory); M. P. JJ-

Anal.: Calcd. for CaHsNCls: C, 42.79; H,3.59; N, 6.24. Found: C, 42.61;H, 3.63; N, 6.33. 1

Example 2 Forty-two grams of 2-methyl-3-(B-ethoxyethyl)-4,6-dihydroxypyridine was dissolved in 200 ml. of freshly distilledphosphorus oxychloride. A small amount of heat was liberated, but therewas no apparent evolution of hydrogen chloride. The solution was heatedin sealed combustion tubes at 140 C. for six hours. When the solutionhad cooled, the excess phosphorus oxychloride was removed under reducedpressure. The oily residue was chilled and a large amount of crushed icewas added rapidly so that no heating occurred. A crystalline materialseparated on short standing, which was filtered and washed, but notdried. The melting point of a dried sample was 55-56" C.

The mother liquor and washes were combined, diluted to about 1500 ml.,and partly neutralized with sodium hydroxide solution until no furtherprecipitation took place. This mixture was extracted twice withchloroform, which extract was washed with water, dried,andsgongentrated. The melting point of the residue was 51- Both solidfractions were combined and dissolved in an excess of petroleum ether. Asmall amount of brown insoluble amorphous material and some water wereremoved. The solution was washed with sodium bicarbonate, with water,was dried, and was concentrated to dryness under reduced pressure. Theyield of 2- methyl-B-(fi-chloroethyl)-4,6-dichloropyridine was 41 g.(86%); M. P. -56 C.

Recrystallization of a sample for analysis from isopropyl alcohol showedno change in melting point.

Example 3 Forty-one grams of 2-methyl-3-(,B-chloroethyl)-4,6-dichloropyridine was dissolvevd in 2000 ml. of methanol and reduced byhydrogen using 30 g. of palladium on barium sulfate as a catalyst. Thereduction was stopped immediately after two moles of hydrogen had beenabsorbed; the time required was about thirty minutes.

After removal of the catalyst, the solution was concentrated to drynessunder reduced pressure leaving a solid residue. The residue,2-rnethyl-3-(fi-chloroethyl)- pyridine was identified by comparison withthat described in the literature; the picrate was prepared, M. P. 135-136 C. (lit. 134-135 C.).

The material was not purified but was hydrolyzed directly, as describedin Example 4.

Example 4 The crude 2-methyl-3-(B-chloroethyl)-pyridine, prepared asdescribed in Example 3, was dissolved in 500 ml. water and heated in aglass-lined autoclave at 160 C. for four hours. The solution wasconcentrated to -100 ml. in volume and made strongly alkaline with solidpotassium hydroxide. This alkaline mixture was extracted with chloroformfor three hours in a continuous extractor. The chloroform extract wasdried and concentrated to a very small volume. An excess of petroleumether was added to the residue, and on scratching, the productcrystallized. It was filtered, washed and dried. The yield of2-methyl-3-(fl-hydroxyethyl)- pyridine was 23 g. over two steps); M. P.62 64 C.

AnaL: Calcd. for CsI-InNO: C, 70.04; H, 8.08; N,

10.21. Found: C, 69.95; H, 8.30; N, 10.01.

The substance was further identified by preparation of severalderivatives:

The benzyl bromide derivative was also prepared by reaction of thepyridine compound with an excess of benzyl bromide at room temperature.The crystalline derivative which separated was recrystallized twice fromethanol; M. P. 155-156 C.

AnaL: Calcd. for C15H1sNOBr: C, 58.44; H, 5.89; N, 4.54. Found: C,58.64; H, 5.95; N, 4.60.

Various changes and modifications in the foregoing procedure will occurto those versed in the art, and to the extent that such changes andmodifications fall within the purview of the appended claims it will beunderstood that they constitute part of our invention.

We claim:

1. The new compound, 2-methyl-3-(fi-chloroethyl)- 4,6-dichloropyridine.

2. The process for preparing 2-methyl-3-(fl-chloio' ethyl)-pyridinewhich comprises reacting 2-methyl-3-(fl-alkoxyethyl)-4,6-dihydroxypyridine with a chlorinating agent fromthe group consisting of phosphorous oxychloride and phosphorouspentachloride at elevated temperature under superatrnospheric pressure,recovering 2 methyl 3 (fi-chloroethyl)-4,6-dichloropyridine from theresulting reaction mixture, intimately contacting said 2-methyl-3([3-chloroethyl)-4,6-dichloropyridine with hydrogen in the presence of apalladium catalyst, and recovering 2-methyl-3 (B-chloroethyl)-pyridinefrom the resulting hydrogenated product.

3. The process for preparing 2-methyl-3-(B-chloroethyl)-pyridine whichcomprises reacting 2-methy1-3-(f3- alkoxyethyl)-4,6-dihydroxypyridinewith phosphorus oxychloride at elevated temperature undersuperatmospheric pressure, recovering 2-methyl-3-( S-chloroethyl)-4,6-dichloropyridine from the resulting reaction mixture, intimatelycontacting said 2 methyl 3 (,8- chloroethyl)-4,6-dichloropyridine withhydrogen in the presence of a palladium catalyst, and recovering 2-methyl-3 (,B-chloroethyD-pyridine from the resulting hydrogenatedproduct.

4. The process for preparing 2-methyl-3-(fi-chloroethyl)-pyridine whichcomprises reacting 2-methyl-3-(fiethoxyethyl)-4,6-dihydroxypyridine withphosphorus oxychloride at elevated temperature under superatmosphericpressure, recovering 2-methyl-3-(fl-chloroethyl)- 4,6-dichloropyridinefrom the resulting reaction mixture, intimately contacting said2-methyl-3(,B-chloroethyl) 4,6-dichloropyridine with hydrogen in thepresence of a palladium catalyst, and recovering Z-methyl-3(B-chloroethyD-pyridine from the resulting hydrogenated product.

5. The process for preparing2-methyl-3-(B-chloroethyl)-4,6-dichloropyridine which comprises reacting2- methyl-3-(B-alkoxyethyl)-4,6-dihydroxypyridine with a chlorinatingagent from the group consisting of phosphorous oxychloride andphosphorous pentachloride under superatrnospheric pressure at anelevated temperature, and recovering2-methyl-3(B-chloroethyl)-4,6-dichloropyridine from the resultingreaction product.

6. The process for preparing2-methyl-3-(B-chloroethyl)-4,6-dichloropyridine which comprises reacting2- methyl-3-(B-ethoxyethyl)-4,6-dihydroxypyridine with a chlorinatingagent from the group consisting of phosphorous oxychloride andphosphorous pentachloride under superatmospheric pressure at an elevatedtemperature, and recovering2-methyl-3(,B-chloroethyl)-4,6-dichloropyridine from the resultingreaction product.

7. The process for preparing2-methyl-3-(B-chloroethyl)-4,6-dichloropyridine which comprises reacting2- methyl 3 (fl-ethoxyethyl)-4,6-dihydroxypyridine with phosphorusoxychloride at a temperature of about 140 C. under superatmosphericpressure, and recovering 2-rnethyl-3(B-chloroethyl)-4,6-dichloropyridine from the resultingreaction product.

8. The process for preparing 2-methyl-3-(j3-chloroethyl)-pyridine whichcomprises reacting 2-methyl-3-(fichloroethyl)-4,6-dichloropyridine withhydrogen in the presence of palladium catalyst, and recovering 2-methyl-3(li-chloroethyD-pyridine from the resulting hydrogenated product.

9. The process for preparing 2-methyl-3-(B-chloroethyl)-pyridine whichcomprises reacting 2-methyl-3-(fichloroethyl)-4,6-dichloropyridine withhydrogen in the presence of a palladium-barium sulfate catalyst, andrecovering 2-methyl-3(B-chloroethyD-pyridine from the resultinghydrogenated product.

No references cited.

2. THE PROCESS FOR PREPARING 2-METHYL-3-(B-CHLOROETHYL) -PYRIDINE WHICHCOMPRISES REACTING 2-METHYL-3(B-ALKOXYETHYL)-4,6-DIHYDROXYPYRIDINE WITHA CHLORINATING AGENT FROM THE GROUP CONSISTING OF PHOSPHOROUSOXYCHLORIDE AND PHOSPHOROUS PENTACHLORIDE AT ELEVATED TEMPERTURE UNDERSUPERATMOSPHERIC PRESSURE, RECOVERING 2- METHYL - 3 -(B-CHLORETHYL)-4,6-DICHLOROPYRIDINE FROM THE RESULTING REACTTION MIXTUREINTIMATELY CONTACTING SAID2-METHYL-3(B-CHLOROETHYL)-4,6-DICHLOROPYRIDINE WITH HYDRROGEN IN THEPRESENCE OF A PALLADIUM CATALYST AND RECOVERING2-METHYL-3-(B-CHLORETHYL)-PYRIDINE FROM THE RESULTING HYDROGENATEDPRODUCT.